Stability of artemisinin in aqueous environments: impact on its cytotoxic action to Ehrlich ascites tumour cells.
We have recently shown artemisinin to be cytotoxic against Ehrlich ascites tumour cells. The aim of this study was to investigate the stability of this compound in the aqueous environment of the in-vitro Ehrlich ascites tumour cell system (RPMI 1640 cell culture medium supplemented with 10% foetal bovine serum (RPMI/FBS) with reference to its cytotoxic action. Literature data show that artemisinin can react with Fe2+ yielding reactive intermediates leaving artemisinin G as a major end-product. The current study showed that only excess addition of Fe2+ to artemisinin in distilled water, phosphate-buffered saline (PBS) and RPMI/FBS and incubation for 24 h led to degradation of artemisinin and yielded artemisinin G. If Fe2+ was not added results from HPLC analysis were indicative of complete recovery of artemisinin from distilled water and RPMI/FBS, with or without cells, at 37 degrees C for at least 24 h. In addition, incubation of artemisinin in RPMI/FBS with or without cells at 37 degrees C for 24 h before cytotoxicity assay did not change its cytotoxic action. On the basis of these results, we suggest that cytotoxicity to tumour cells was caused by unchanged artemisinin. This is not so for the antimalarial activity of artemisinin and derivatives, for which the presence of a pool of (haem) Fe2+ is a prerequisite resulting in free radicals or electrophilic intermediates or both.
Beekman
A C
AC
Department of Pharmaceutical Biology, Groningen Institute for Drug Studies, University of Groningen, The Netherlands.
Woerdenbag
H J
HJ
Van Uden
W
W
Pras
N
N
Konings
A W
AW
Wikström
H V
HV
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000032:analysis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D037621:Artemisinins; D002286:Carcinoma, Ehrlich Tumor / Q000188:drug therapy; D002417:Cattle; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D017077:Culture Media, Conditioned; D004347:Drug Interactions; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D005296:Ferrous Compounds / Q000737:chemistry*; D008401:Gas Chromatography-Mass Spectrometry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D012717:Sesquiterpenes / Q000032:analysis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D037621:Artemisinins; D017077:Culture Media, Conditioned; D005296:Ferrous Compounds; D012717:Sesquiterpenes; C110815:artemisinin G; C031327:artemisinin